Metabolic kinetics of MN9202 in Beagle dog liver microsomes.
- Author:
Zhi-fu YANG
1
;
Si-yuan ZHOU
;
Qi-bing MEI
;
Tie-hong YANG
;
Zhen-guo LIU
Author Information
- Publication Type:Journal Article
- MeSH: Animals; Aryl Hydrocarbon Hydroxylases; antagonists & inhibitors; Calcium Channel Blockers; metabolism; pharmacokinetics; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A Inhibitors; Dihydropyridines; metabolism; pharmacokinetics; Dogs; Ketoconazole; pharmacology; Microsomes, Liver; metabolism; Mixed Function Oxygenases; antagonists & inhibitors; Nitrobenzenes; metabolism; pharmacokinetics; Tranylcypromine; pharmacology; Troleandomycin; pharmacology
- From: Acta Pharmaceutica Sinica 2005;40(11):1019-1023
- CountryChina
- Language:Chinese
-
Abstract:
AIMTo study the metabolic kinetics of MN9202 in Beagle dog liver microsome.
METHODSBeagle dog liver microsomes were prepared by using ultracentrifuge method. After incubating 0.4 micromol x L(-1) MN9202 with 1 g x L(-1) microsomes for 30 min at 37 degrees C, the reaction was terminated by adding 0.5 mL alkalization. The RP-HPLC was used to determine the drug in the incubation mixture. The Michaelis-Menten parameters Km, and Vmax in Beagle dog liver microsomes were initially estimated by analyzing Lineweave-Brurk plot. Various selective CYP inhibitors were used to investigate their inhibitory effect on the metabolism of MN9202.
RESULTSThe Km, Vmax and CLint of MN9202 were (22.6 +/- 8.0) micromol x L(-1), (0.54 +/- 0.17) micromol x g(-1) x min(-1) and (0.0242 +/- 0.0009) L x g(-1) x min(-1), respectively. The metabolism of MN9202 was significantly inhibited by ketoconazole (Ket) and troleandomycin (Tro) in Beagle dog liver microsomes. Tranylcypromine (Tra) could inhibit the metabolism of drug as well. While other inhibitors showed little inhibitory effect on the metabolism of MN9202.
CONCLUSIONIt was shown that CYP3A and CYP2C19 were involved in MN9202 metabolism. The inhibitors of human CYP3A and CYP2C19 may have potential interaction with MN9202, and this can reduce the metabolism rate and increase the toxicity of MN9202.
